What Are MGUS, Smoldering Multiple Myeloma, and Active Myeloma?

Patients must undergo a careful diagnostic workup to stage their disease. Before developing active myeloma, patients pass through two earlier disease stages. These precursor stages are monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). 

Table Defining MGUS, SMM, and Active Myeloma

	MGUS (benign)	SMM (pre-malignant)	Myeloma (malignant)
Clonal plasma cells in bone marrow	<10%	10%-60%	≥10%
Presence of myeloma-defining events	none	none	yes
Likelihood of progression	~1% per year	~10% per year	not applicable
Treatment of obervation	observation only	observation; treatment*	treatment

*Treatment in the setting of clinical trial or for high-risk patients likely to progress to active myeloma within 2 years.

Monoclonal Gammopathy of Undetermined Significance, or MGUS 

If you have been diagnosed with or are suspected to have MGUS, see an experienced hematologist. A hematologist is a doctor who specializes in the problems of blood and bone marrow. 

Some facts about MGUS 

• MGUS occurs in 3% to 5% of the population in the United States.  
• This rate is higher for those who are 50 years of age or older. 
• MGUS is the earliest disease state associated with the subsequent development of myeloma. 

What Are the Types of MGUS?

This webpage discusses the plasma cell type of MGUS, which comprises 85% of all MGUS cases. Yet, MGUS can arise from either plasma cells or lymphoid cells, and these two types of MGUS are biologically different. 

Plasma cell type MGUS 

This type of MGUS can progress to become myeloma or a related disorder, including amyloidosis and light chain deposition disease (LCDD). Plasma cells develop from a type of white blood cell (WBC) called B cells (B lymphocytes) and are a key part of the immune system. In the normal immune response, B cells mature into plasma cells in the bone marrow. In bone marrow, plasma cells produce antibodies that attach to antigens that enter the body. 

How Is MGUS Diagnosed? 

Patients with MGUS have comparatively low levels of monoclonal protein (myeloma protein, M-protein) in the serum and/or urine. Bone marrow plasma cell levels are less than 10%. SLiM-CRAB criteria features are absent. 

The laboratory tests used to measure the amount of M-protein are serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP). 

The amount of M-protein reflects the activity of abnormal plasma cells in the bone marrow. SPEP and/or UPEP should be repeated 3 to 6 months after MGUS is diagnosed. If your level of M-protein remains stable and there are no symptoms or other health changes, your doctor can extend the time between follow-up testing. Be sure to report any change in your health to your doctor. 

Immunofixation electrophoresis (IFE) is an immunologic test of the serum or urine used to identify the exact heavy-chain and light-chain type of M-protein that is present. Your plasma cells can produce one of five classes (isotypes) of immunoglobulin (Ig). If you have the IgM type of M-protein, ask your doctor about a computed axial tomography (CAT or CT) of the abdomen to check for lymph node enlargement. 

An immunoglobulin light chain is the smaller of two units that make up an antibody. There are two types of light chain: kappa and lambda. A light chain may be bound to a heavy chain by chemical bonds. It could also be unbound and “free” to enter the bloodstream. 

Free light chains circulate in the blood are small enough to pass into the kidneys. There, they may be filtered out into the urine or may stick together and block the kidney’s tubules. For more information about free light chains and the test used to quantify them, read the IMF’s publication Understanding Freelite® and Hevylite® Tests. 

If testing reveals evidence of myeloma or Waldenström macroglobulinemia (WM), you will be tested for levels of lactate dehydrogenase (LDH), beta-2 microglobulin (β2 microglobulin, β2M, or β2M), and C-reactive protein (CRP). See Tests to assess proteins and other substances in the blood to learn more. 

If the test results are within normal ranges, you will be tested again in 6 months with SPEP and a complete blood count (CBC), and then annually for life or until any changes occur. 

If MGUS is diagnosed or suspected, then additional testing may be performed at the discretion of your doctor. This includes bone marrow testing and imaging studies of bone (to rule out early bone disease). 

A bone marrow biopsy is always required if the patient has unexplained hypercalcemia, kidney dysfunction, anemia, bone lesions, or a suspicion of amyloid light‑chain (AL) amyloidosis. 

For a diagnosis of MGUS, all of the following criteria must be met: 

1. Presence of M-protein in the serum < 3 g/dL, 
2. Presence of monoclonal plasma cells in the bone marrow < 10%, and 
3. Absence of CRAB criteria. 

For a diagnosis of light chain MGUS, all of the following criteria must be met: 

1. Abnormal free light chain (FLC) ratio < 0.26 or > 1.65, 
2. Level of the appropriate involved light chain (increased kappa FLC in patients with ratio > 1.65 and increased lambda FLC in patients with ratio < 0.26), 
3. No immunoglobulin heavy chain expression on IFE, 
4. Absence of CRAB criteria, 
5. Presence of monoclonal plasma cells in the bone marrow < 10%, and 
6. Presence of M-protein in the urine based on a 24-hour collection < 500 mg. 

 

What Is the Risk Progression of MGUS to Myeloma?

 

Progression from MGUS to active myeloma occurs at the low rate of only 1% per year. All patients who develop myeloma have previously had MGUS followed by smoldering multiple myeloma (SMM). Researchers are gaining a better understanding of the biologic events that take place when MGUS develops into myeloma. Yet, it is not yet known what triggers the progression in some patients but not in others, or how to prevent progression.  

The IMF International Myeloma Working Group (IMWG) has established the following risk factors for MGUS progressing to myeloma: 

1. M-protein level is more than 1.5 g/dL (can also be written as 15 g/L), 
2. M-protein type is IgA or IgM, and 
3. Abnormal FLC ratio of kappa to lambda FLCs. 

 

Risk of progression from MGUS to active myeloma: 

• Low-intermediate-risk MGUS has one of the risk factors. 
• High-intermediate-risk MGUS has two of the risk factors. 
• High-risk MGUS has all three of the risk factors. 

 

 

 

If you are diagnosed with intermediate-risk or high-risk MGUS during your baseline testing, you should also have a bone marrow aspiration and bone marrow biopsy. The same bone marrow sample that is obtained should also be used for cytogenetic studies. Visit Tests to assess monoclonal protein to learn about the tests used to identify and quantify M-protein.

How Should MGUS Be Managed? 

At this time, there is no treatment for MGUS. Monitoring MGUS as described above can determine if any progression is occurring and if any additional testing is required. The risk of progression is 1% per year. The majority of MGUS patients are monitored without the need for additional medical attention for many years.

 

What Is Smoldering Multiple Myeloma? 

Smoldering multiple myeloma (SMM) is an asymptomatic (no signs or symptoms) precursor state of active myeloma, similar to MGUS but at a higher level of disease. The average risk of progression from SMM to myeloma is 10% per year. Unlike active myeloma, patients with SMM do not have CRAB criteria features indicating organ damage. Patients with SMM should be observed by a hematologist-oncologist at regular intervals. 

What Are the Diagnostic Criteria for Smoldering Multiple Myeloma? 

For a diagnosis of SMM, both of the following criteria must be met: 

1. Presence of M-protein in the serum (IgG or IgA) ≥ 3 g/dL, or urinary  M-protein ≥ 500 mg per 24-hour collection, and/or presence of  monoclonal plasma cells in the bone marrow 10%–60%, and
2. Absence of myeloma-defining events (MDE) or amyloidosis. 

Myeloma-defining events (MDE) include the following: 

• Presence of CRAB criteria, 
• Presence of monoclonal plasma cells in the bone marrow ≥ 60%, 
• Ratio of involved-to-uninvolved serum FLC ≥ 100 (involved FLC level must be ≥ 100 mg/L and urine M-protein level must be at least 200 mg per 24-hour collection on UPEP), and 
• One or more focal lesions on magnetic resonance imaging (MRI) studies. 

The Mayo Clinic’s 2/20/20 Criteria 

In 2018, the Mayo Clinic published the 2/20/20 criteria. These criteria are based on patients who had none, one, or two to three of the risk factors that were most associated with a short time to progression from SMM to active myeloma: 

• Serum M-protein > 2 g/dL, 
• Bone marrow plasma cell (BMPC) infiltration > 20%, and/or 
• Ratio of involved-to-uninvolved serum FLC > 20. 

SMM may be diagnosed in the following scenarios: 

• In a patient who is being observed for MGUS, 
• In an individual seeking healthcare due to an unrelated condition, or 
• During a regular medical examination. 

Once SMM is diagnosed, current clinical guidelines recommend stratification to determine the risk of progression to myeloma and lifelong monitoring for progression. 

The current understanding of the biology and behavior of SMM enables doctors to avoid treating patients who do not need to be treated, but to intervene promptly if a patient is at a high risk of progression to myeloma. 

The doctor’s experience and judgment are crucial to differentiating MGUS from SMM and from active myeloma. A primary consultation or second opinion with a myeloma expert is highly recommended. 

The diagnostic process in monitoring SMM 

The diagnostic process includes SPEP, CBC, and measurement of calcium and creatinine values.  

• Twenty-four-hour urine collection for electrophoresis and immunofixation should be performed at diagnosis and within 2 to 3 months after the initial recognition of SMM. 
• A baseline bone marrow biopsy and skeletal survey must be performed. 
• An MRI of the spine and pelvis are highly recommended because these sensitive studies are better able to predict for more rapid progression to active myeloma. 
• Skeletal X-rays are no longer the standard of care in the diagnostic process of SMM because they only pick up bone lesions after approximately 30% of the cancellous bone has been destroyed. Whole-body low-dose CT (WBLDCT) is now the standard of care to detect and document early bone disease. WBLDCT is the preferred baseline imaging study for newly diagnosed myeloma because it does not require the use of contrast agents and  uses much less radiation than conventional CT. 

How Are Patients with Smoldering Multiple Myeloma Monitored? 

Patients with SMM are monitored more frequently than patients with MGUS because the risk of progression to active myeloma is higher.  

• If you have been diagnosed with SMM, you must be carefully evaluated by a hematologist-oncologist every 4 to 6 months for the first year.  
• If your SMM remains stable after a year, the evaluation can be lengthened to every 6 to 12 months based on your SMM status and your doctor’s judgment. 

 

When Might SMM Progress to Active Myeloma? 

Ongoing research is being conducted to identify the risk factors for progressing from SMM to active myeloma. A system of precise criteria does not exist now. 

In 2014, The Lancet published the IMWG updated criteria for the diagnosis of myeloma. SMM patients with 80% or greater risk of progression to myeloma within 2 years were defined as having early active myeloma. To help prevent the development of end-organ damage, a patient should be treated for myeloma if any of the myeloma-defining events (MDE) are present. 

In 2018, Blood Cancer Journal published a statistical analysis of variables among patients with SMM at Mayo Clinic in Rochester, Minnesota. Further refinements to the 2/20/20 criteria were made with the addition of the following two high-risk factors: 

• chromosomal abnormality +1q (a gain of chromosome 1q), 
• chromosomal abnormality del13q (a deletion of chromosome 13q). 

If one or both of these abnormalities are found by fluorescence in situ hybridization (FISH) testing of myeloma cells, the risk of disease progression is increased. 

In 2020, Blood Cancer Journal published the IMWG risk stratification model for SMM that can be applied across the globe using easily available data. 

Dr. María-Victoria Mateos and colleagues assembled an international cohort of 1,996 patients with SMM who met the revised IMWG criteria. Patients with ≥ 80% risk of progression at 2 years were excluded because they are considered to have active myeloma by current definition. 

Three independent factors were identified predicting high-risk SMM (HR SMM) progression to active myeloma at 2 years based on the 2/20/20 criteria. This translates into 3 categories with an increasing 2-year progression risk: 

• 6% for low-risk patients with no risk factors, 
• 18% for intermediate-risk patients who have 1 factor, and 
• 44% for high-risk patients who have 2 or more factors). 

In addition, presence of chromosomal abnormalities t(4;14), t(14;16), +1q, and/or del13q allowed for further separation into the following 4 groups: 

1. Low-risk SMM patients had no cytogenetic abnormalities. Low risk of progression to active myeloma. 
2. Low intermediate-risk SMM patients with 1 cytogenetic abnormality had the progression risk at 2 years of 23%. 
3. Intermediate-risk SMM patients with 2 cytogenetic abnormalities had the progression risk at 2 years of 46%. 
4. High-risk SMM (HR SMM) patients with 3 or more cytogenetic abnormalities had the progression risk at 2 years of 63%. 

 

What Is the Treatment for Smoldering Multiple Myeloma? 

Typically, SMM is not treated. There are no standardized treatment options for patients with SMM. 

Currently, a number of clinical trials are investigating SMM, including studies launched with the support of the IMF Black Swan Research Initiative®. 

• A clinical trial is a medical research study with people who volunteer to test scientific approaches to a new treatment or a new combination therapy. 
• Each clinical trial is designed to find better ways to prevent, detect, diagnose, or treat cancer and to answer scientific questions. 

If you have SMM and are interested in taking part in a clinical trial, discuss your options with your doctor. You must have a clear understanding of your relative risk of progression to active myeloma and of the potential risks and benefits of treatment in your particular case, including the psychological aspects of treatment as opposed to observation. 

 

What Is Active Myeloma? 

Myeloma is a cancer of the bone marrow plasma cells, white blood cells that make antibodies. Cancer is a term for diseases in which malignant cells divide without control. Cancer cells can invade nearby tissues and spread through the bloodstream and lymphatic system to other parts of the body. Malignant plasma cells are called myeloma cells. 

If your SMM is progressing to active myeloma, this is a key time to seek an opinion (or a second opinion) from a myeloma specialist. A local hematologist or oncologist might see a few myeloma patients or none at all. Myeloma specialists at large “high-volume” treatment centers and large academic institutions see hundreds of myeloma patients, conduct clinical trials with new drugs and new combination therapies, and develop the expertise needed to make appropriate decisions. 

A diagnosis of active myeloma is made when the patient experiences the following: 

• 10% or more clonal plasma cells in bone marrow, and 
• at least one myeloma-defining event (MDE).  

Myeloma is a highly individual disease. Often, it is slow-moving. Sometimes, it can be very aggressive. The urgency of treatment depends upon the exact problems faced by an individual patient. An experienced myeloma specialist can tailor a treatment approach best suited to your specific situation, as well as anticipate and prevent or mitigate treatment-related problems. 

Many highly effective therapies are approved for the treatment of myeloma by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and by other regulatory agencies. New approvals are expanding treatment options and the rate of development of new drugs continues to accelerate. 

Many patients with myeloma lead full and productive lives for years, even decades, after diagnosis. Survival and quality of life of myeloma patients are improving steadily. Learning about myeloma and understanding how it is treated can help patients and their loved ones reduce their anxiety, and gain a sense of control. Overall, it makes it easier to come to terms with the diagnosis. 

 

 

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